FIDES-01: Derazantinib in Subjects With FGFR2 Gene Fusion-, Mutation- or Amplification- Positive Inoperable or Advanced Intrahepatic Cholangiocarcinoma

Sponsor

Basilea Pharmaceutica (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03230318

Collaborator

(none)

148

Enrollment

Locations

Arm

57.7

Anticipated Duration (Months)

3.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This pivotal, open-label, single-arm study will evaluate the anti-cancer activity of derazantinib by Objective Response Rate (ORR) by central radiology review as per RECIST v1.1 in subjects with inoperable or advanced intrahepatic cholangiocarcinoma (iCCA) whose tumors harbor FGFR2 gene fusions (by FISH performed by the central laboratory) or FGFR2 gene mutations or amplifications (based on NGS testing performed or commissioned by the respective study center) and who received at least one prior regimen of systemic therapy. Subjects will be dosed orally once per day at 300 mg of derazantinib capsules.

Condition or Disease	Intervention/Treatment	Phase
Intrahepatic Cholangiocarcinoma Combined Hepatocellular and Cholangiocarcinoma	Drug: derazantinib	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

148 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Pivotal Study of Derazantinib in Patients With Inoperable or Advanced Intrahepatic Cholangiocarcinoma and FGFR2 Gene Fusions or FGFR2 Gene Mutations or Amplifications

Actual Study Start Date :

Nov 10, 2017

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Sep 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: derazantinib Oral administration	Drug: derazantinib derazantinib will be orally administered at 300 mg once per day one hour prior to or two hours after a meal and is supplied as 100 mg capsules.

Arm

Intervention/Treatment

Experimental: derazantinib

Oral administration

Drug: derazantinib

derazantinib will be orally administered at 300 mg once per day one hour prior to or two hours after a meal and is supplied as 100 mg capsules.

Outcome Measures

Primary Outcome Measures

Substudy 1: Anti-cancer activity of derazantinib by Objective Response Rate (ORR) [Up to approximately 32 weeks]
ORR will be assessed by central radiology review as per RECIST version 1.1
Substudy 2: Anti-tumor activity of derazantinib by Progression Fress Survival at 3 months (PFS 3) [3 months]
PFS 3 will be assessed based on survival status or central radiology review (Response Evaluation Criteria in Solid Tumors, RECIST 1.1)

Secondary Outcome Measures

Safety of derazantinib as assessed by adverse events [Up to approximately 36 weeks]
Adverse events will be graded using NCI CTCAE guidelines, version 4.03
Anti-cancer activity of derazantinib by duration of response (DoR) [Up to approximately 32 weeks]
DoR will be assessed by central radiology review per RECIST version 1.1
Anti-cancer activity of derazantinib by progression free survival (PFS) [Up to approximately 32 weeks]
PFS will be assessed by central radiology review per RECIST version 1.1
Anti-cancer activity of derazantinib by overall survival (OS) [Up to approximately 36 weeks]
OS will be calculated from the first date of receiving study drug until death
Health-related quality of life as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire [Up to approximately 36 weeks]
Health-related quality of life as assessed by the EORTC QLQ-BIL21 questionnaire [Up to approximately 36 weeks]
Health-related quality of life as assessed by the EuroQol EQ-5D questionnaire [Up to approximately 36 weeks]
Substudy 2: Anti-cancer activity of derazantinib by Objective Response Rate [Up to approximately 32 weeks]
ORR will be assessed by central radiology review as per RECIST version 1.1

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed written informed consent granted prior to initiation of any study-specific procedures
18 years of age or older
Histologically or cytologically confirmed locally advanced, inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-cholangiocarcinoma [cHCC-CCA])
Substudy 1: FGFR2 fusion status based on the following assessments:

If central laboratory designated by Sponsor: Positive FISH test; and/or b) If non-central laboratory: i) Positive FISH or NGS test: patients may be enrolled and may start dosing, but central confirmation is required* ii) Negative FISH or NGS test: tissue may be submitted to the central laboratory designated by the Sponsor, and patients may only be enrolled if the central test is positive

*Using standard protocols and approved by local IRB/EC, by CLIA or other similar agency.

Substudy 2: FGFR2 mutation/amplification status based on local NGS testing performed or commissioned by the respective study site.

Received at least one regimen of prior systemic therapy and then experienced documented radiographic progression
Measurable disease by RECIST version 1.1 criteria
ECOG performance status ≤ 1
Adequate organ functions as indicated by the following laboratory values (based on screening visit values from the central laboratory).

Hematological
Hemoglobin (Hgb) ≥ 9.0 g/dL
Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
Platelet count ≥ 75 x 109/L
International normalized ratio (INR) 0.8 to upper limit of normal (ULN) or ≤ 3 for subjects receiving anticoagulant therapy such as Coumadin or heparin
Hepatic
Total bilirubin ≤ 2 x ULN
AST and ALT ≤ 3 ULN (≤ 5 x ULN for subjects with liver metastases)
Albumin ≥ 2.8 g/dL
Renal
Serum creatinine ≤ 1.5 x ULN
Creatinine clearance of ≥ 30 mL/min as estimated by the Cockcroft-Gault equation

Female and male patients of child-producing potential must agree to avoid becoming pregnant or impregnating a partner, respectively, use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse, during the study*, and until at least 120 for 90 days after the last dose of derazantinib.

*From the day of first study medication, or for oral contraception from 14 days before first study medication.

Male patients are considered not to be of child-producing potential if they have azoospermia (whether due to vasectomy or an underlying medical condition). Female patients are considered not to be of child-producing potential if they are:

postmenopausal* , or
have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening, or
have a congenital or acquired condition that prevents childbearing.

Male or female patients of child-producing potential must agree to comply with one of the following until at least 120 days after the last dose of derazantinib:

Abstinence from heterosexual activity**
Using (or having their partner use) an acceptable method of contraception during heterosexual activity. Acceptable methods of contraception are***:

any ONE of:
an intrauterine device (IUD)
vasectomy of a female patient's male partner
a contraceptive rod implanted into the skin.
any TWO in combination of:
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
cervical cap with spermicide (nulliparous women only)
contraceptive sponge (nulliparous women only)
male condom or female condom (cannot be used together)
hormonal contraceptive (oral contraceptive pill [estrogen/progestin pill or progestin-only pill], contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection)

*Postmenopausal is defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post -menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is not sufficient.

Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region.

Exclusion Criteria:

Receipt of treatment before the first dose of study drug (Cycle 1 Day 1) within an interval shorter than the following, as applicable:

One chemotherapy or biological (e.g., antibody) cycle interval
Five half-lives of any small-molecule investigational or licensed medicinal product
Two weeks, for any investigational medicinal product with an unknown half-life
Four weeks of curative radiotherapy
Seven days of palliative radiotherapy
28 days of radiotherapy

Major surgery, locoregional therapy, or radiation therapy within four weeks of the first dose of derazantinib
Previous treatment with any FGFR inhibitor (e.g., Balversa® [erdafitinib], Pemazyre® [pemigatinib], infigratinib, rogaratinib, futibatinib, lenvatinib, ponatinib, dovitinib, nintedanib, AZD4547, LY2784455).

Subjects who received less than four weeks of therapy and were unable to continue therapy due to toxicity will be allowed to participate

Unable or unwilling to swallow the complete daily dose of derazantinib capsules
Clinically unstable central nervous system (CNS) metastases (to be eligible, subjects must have stable disease ≥ 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications)
Current evidence of clinically significant corneal or retinal disorder likely to increase the risk of eye toxicity, including but not limited to bullous/band keratopathy, keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion, inflammation/ulceration, confirmed by ophthalmologic examination.
Concurrent uncontrolled or active hepatobiliary disorders, untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, biloma or abscess (to be eligible, the subjects have to be treated and disorders/complications should be resolved within 2 weeks prior to the first dose of derazantinib)
History of significant cardiac disorders:

Myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of derazantinib (MI that occurred > 6 months prior to the first dose of derazantinib will be permitted)
QTcF >450 msec (males or females)

Serum electrolyte abnormalities defined as follows:

Hyperphosphataemia: Serum phosphate > institutional ULN
Hyperkalemia: > 6.0 mmol/L
Hypokalemia: < 3.0 mmol/L
Hypercalcemia: corrected serum calcium < 1.75 mmol/L (< 7.0 mg/dL)
Hypocalcemia: corrected serum calcium > 3.1 mmol/L (> 12.5 mg/dL)
Hypomagnesemia: < 0.4 mmol/L (< 0.9 mg/dL)

Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of derazantinib (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)
History of additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer.
Concurrent uncontrolled illness not related to cancer, including but not limited to:

Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements
Known uncontrolled human immunodeficiency virus (HIV) infection
Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication at the time of first dose of study drug administration

Blood or albumin transfusion within 5 days of the blood draw being used to confirm eligibility
Pregnant or breast feeding
Known hypsersensitivity to derazantinib, or to any of the study drug excipients (starch, lactose, crospovidone, magnesium stearate)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Phoenix	Arizona	United States	85054
2	Mayo Clinic	Jacksonville	Florida	United States	32224
3	Moffitt Cancer Center	Tampa	Florida	United States	33612-9416
4	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
5	Mayo Clinic	Rochester	Minnesota	United States	55905
6	Memorial Sloan Kettering Cancer Center - Sidney Kimmel Center for Prostate and Urologic Cancers	New York	New York	United States	10065-6800
7	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
8	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
9	The University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
10	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
11	University of Washington Medical Center	Seattle	Washington	United States	98109
12	Hôpital Erasme	Brussels		Belgium	1070
13	Cliniques Universitaires Saint-Luc	Brussels		Belgium	1200
14	Antwerp University Hospital	Edegem		Belgium	2650
15	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
16	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
17	CHU Grenoble Alpes	La Tronche		France	38700
18	Gustave Roussy	Villejuif		France	94805
19	Universitätsklinikum Frankfurt	Frankfurt am Main		Germany	60590
20	Universitätsklinikum Hamburg-Eppendorf (UKE)	Hamburg		Germany	20246
21	Medizinische Hochschule Hannover (MHH)	Hannover		Germany	30625
22	Universitätsklinikum des Saarlandes	Homburg		Germany	66421
23	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz		Germany	55131
24	St. James's Hospital	Dublin		Ireland	D08 NHY1
25	Sant'Orsola-Malpighi Hospital, University of Bologna	Bologna		Italy	40138
26	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan		Italy	20133
27	Ospedale San Gerardo	Monza		Italy	20900
28	Istituto Oncologico Veneto - IRCCS	Padova		Italy	35128
29	Azienda Ospedaliero-Universitaria Pisana	Pisa		Italy	56126
30	Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS	Rozzano		Italy	20089
31	Seoul National University Hospital	Seoul		Korea, Republic of	3080
32	Samsung Medical Center	Seoul		Korea, Republic of	6351
33	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	6591
34	Vall d'Hebrón University Hospital	Barcelona		Spain	08035
35	Catalan Institute of Oncology	Barcelona		Spain	08908
36	Hospital General Universitario Gregorio Marañón	Madrid		Spain	28007
37	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
38	Universitätsspital Basel	Basel		Switzerland	4031
39	University College London Hospitals NHS Foundation Trust	Euston		United Kingdom	NW1 2BU
40	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G120YN
41	The Royal Marsden	Sutton		United Kingdom	SM2 5PT